Similarly, elevation of cAMP in vascular smooth muscle by activation of β-adrenergic receptors or adenosine receptors promotes vasodilation through multiple mechanisms, including (1) decreased affinity of MLCK for Ca++/ calmodulin, (2) decreased cytosolic [Ca++] concentration, and/or (3) increased MP activity. The decreased affinity of MLCK for Ca++/calmodulin following elevation of cAMP involves protein kinase A (PKA)-dependent phosphorylation of MLCK. The ability of PKA to reduce cytosolic [Ca++] is complex and can involve activation of potassium channels (e.g., ATP-dependent potassium channels), resulting in hyperpolarization of the smooth muscle and hence decreased Ca++ influx through voltage-gated Ca++ channels. cAMP has also been shown to increase the frequency of Ca++ sparks in vascular smooth muscle, which as described earlier, hyperpolarizes the membrane potential by activation of Ca++-gated K+ channels, thereby reducing the influx of Ca++ through voltage-gated Ca++ channels. cAMP can also promote relaxation of smooth muscle by increasing the activity of MP (through either PKA-dependent phosphorylation of a subunit of MP or through inhibition of ROK). Inhibition of ROK can occur through PKA-dependent phosphorylation or through a signaling pathway involving the cAMP-modulated guanine nucleotide exchange factor Epac (exchange protein directly activated by cAMP)
Relaxation of smooth muscle by elevation of cAMP has afforded asthmatics a means of reversing bronchiolar constriction with use of β2-adrenergic agonists. The local vasodilatory effect of adenosine produced in working muscle during periods of intense exercise has also been attributed at least in part to elevated cAMP levels in vascular smooth muscle secondary to adenosine-induced stimulation of purinergic receptors on the sarcolemma of vascular smooth muscle. Adenosine may also activate a sarcolemmal K+ channel to induce membrane hyperpolarization, which as already noted will decrease the influx of Ca++ through voltage-gated Ca++ channels and cause vasodilation. Thus regulation of smooth muscle tone may be under the influence of not only the autonomic nervous system and circulating hormones but also neighboring endothelial cells and skeletal muscle cells via diffusible substances such as NO and adenosine.